MIS-C Update for Pediatricians

Asif Noor, MD, FAAP

Selina Bowler, MD

Dr. Asif Noor, MD, FAAP is a Pediatric Infectious Disease Specialist at NYU Winthrop Hospital and he co-chairs the Infectious Disease Committee of the NYS AAP Chapter 2.

Dr. Selina Bowler is a Fellow in Infectious Diseases at NYU Long Island.

COVID-19 pandemic brought a unique challenge to pediatricians in the form of a post-inflammatory condition followed by acute COVID-19 infection in children.  It was termed by the Centers for Disease Control and Prevention as multisystem inflammatory syndrome in children (MIS-C) in May 2020.

The emergence of MIS-C cases in the New York region succeeded the peaks of spring and winter COVID outbreaks by 2-4 weeks.  In the New York State, there have been between 200-249 reported cases, with between 150-199 reported cases in New York City alone.  Nationally, as of October 4, 2021, there have been 5,217 reported cases and a total of 46 MIS-C deaths in the US.

What do we know about MIS-C?

CDC Case Definition for MIS-C: https://emergency.cdc.gov/han/2020/han00432.asp

Based on current CDC data, MIS-C cases so far appear to be more common in males (60.1%), Black and Hispanic/Latinx individuals (61.1%), and children aged 6-11 years (38.6%) with a median age of 9 years.

The exact mechanisms at play in MIS-C are currently unknown.  However, the majority of children have serologic evidence of infection with SARS-CoV-2, suggesting a post-infectious etiology.  This is further supported by the timing of presentation following the rise in COVID-19 cases and high SARS-CoV-2 cycle thresholds found in patients with MIS-C.  Evidence from several smaller studies exploring immunologic features of MIS-C compared to COVID-19 suggests T-cell-biased lymphopenia and increased T-cell activation, including increased activation of vascular patrolling CD8+ T-cells.

Spectrum of disease

Based on the current literature of MIS-C, the spectrum of disease severity appears to range from a milder febrile inflammatory state to Kawasaki disease-like illness and severe disease with multiorgan involvement presenting with shock.

MIS-C Presentation Compared to Severe Covid-19 in Children

The February 2021 JAMA article by Feldstein and colleagues compares MIS-C and severe pediatric COVID-19 infections and found that MIS-C patients were more likely to be without underlying conditions.  Common initial presenting signs and symptoms in MIS-C compared to severe COVID-19, respectively, included constitutional (99.4% vs 81.8%), gastrointestinal (90.2% vs 57.5%), mucocutaneous (66.8% vs 10.2%), upper respiratory (34.1% vs 32.1%), lower respiratory (43.0% vs 62.2%) and neurologic (40.4% vs 32.2%) involvement.  MIS-C patients were more likely to have mucocutaneous findings, cardiovascular involvement, and more severe inflammation (i.e. higher median neutrophil-to-lymphocyte ratio [NLR] and CRP levels, lower platelet counts).  Additionally, patients presenting with NLR >5, platelets <150,000, and/or CRP >100 within 48 hours of admission were more likely to be diagnosed with MIS-C versus severe COVID-19 infection.

Management

Who to Evaluate?

Most institutions in New York State have established protocols for the evaluation of suspected cases of MIS-C.  These clinical pathways mirror the American Academy of Pediatrics (AAP) guidelines with few changes tailored to the institutional workflow.

According to AAP, children presenting with fever for ≥3 days without another clear diagnosis who are ill-appearing or with GI symptoms, rash, conjunctivitis, oral mucosal changes, extremity changes, neurologic or psychiatric symptoms and/or lymphadenitis should be evaluated for possible MIS-C.

How to evaluate (A 2 Tier Approach)

At NYU, we use a 2-tier approach to evaluate suspected MIS-C cases, similar to the AAP and American College of Rheumatology (ACR)’s clinical guidance on MIS-C and hyperinflammation in pediatric COVID-19.

Per NYU protocol, Tier 1 evaluation includes CBC, CMP, CRP, troponin, and EKG in addition to any other pertinent labs for the individual clinical scenario.  All suspected MIS-C patients should get tested for SARS-CoV-2 PCR and SARS-CoV-2 serology.  Other tests to be considered include blood culture, urinalysis with reflex urine culture, and/or respiratory viral panel to exclude other etiologies.

If troponin is elevated, obtain BNP (B-type natriuretic peptide) level, consult Pediatric Cardiology service, and proceed with Tier 2 evaluation.  If CRP >20 mg/L and alternative diagnoses have been ruled out, proceed with Tier 2 evaluation.  Tier 2 evaluation includes VBG with lactate, D-dimer, troponin, ESR, procalcitonin, LDH, PT/PTT, ferritin, respiratory viral panel, urinalysis, blood cultures (if not already done).  Additionally, include BNP, COVID PCR and IgG levels and CXR if not obtained during Tier 1 evaluation.

NYU’s Tier 1 evaluation includes initial workup to assess cardiac function (i.e. troponin and EKG), whereas AAP and ACR recommends assessing cardiac function as part of Tier 2 evaluation.

Who to treat?

Cases of mild inflammation are typically managed with supportive care only.  Treatment of moderate to severe cases is based on the phenotype.

What’s new on the treatment front?

In June 2021, NEJM published an article on the initial therapy and outcomes for MIS-C and found that giving IVIG and steroids as initial therapy decreased risk of new or persistent cardiovascular dysfunction by decreasing risk of LV dysfunction and shock requiring vasopressor support when compared to IVIG alone.  Patients who were initially treated with IVIG and steroids were also less likely to receive adjunctive therapy compared to those initially treated with IVIG alone.  Concurrent initial treatment of IVIG and steroids did not affect risk of fever compared to IVIG alone.  Thus, in those initially presenting with signs and symptoms of cardiac dysfunction, it is recommended to start initial therapy with IVIG and steroids together.

In a pre-print retrospective cohort study published by Vukomanovic and colleagues (due for publication November 2021) in the Pediatric Journal of Infectious Disease, initial treatment with corticosteroids in patients with MIS-C-associated cardiovascular dysfunction was associated with more rapid normalization of LVEF, fever and CRP levels and shorter ICU stays when compared to initial IVIG therapy.  Furthermore, patients in the study initially treated with IVIG alone had higher prevalence of treatment failure compared to those initially treated with corticosteroids.

Based on these studies, it is suggested that those with evidence of cardiac involvement at presentation should be initially treated with corticosteroids.

REFERENCES

1. CDC Reported MIS-C Cases: https://covid.cdc.gov/covid-data-tracker/#mis-national-surveillance
2. CDC MIS-C Case Definition: https://emergency.cdc.gov/han/2020/han00432.asp
3. Diorio C, Henrickson SE, Vella LA, et al. Multisystem inflammatory syndrome in children and COVID-19 are distinct presentations of SARS-CoV-2. J Clin Invest 2020; published online July 30. https://doi.org/10.1172/JCI140970
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